Anticorpos contra LDL-ox e síndrome coronariana aguda

FUNDAMENTO: A oxidação da lipoproteína de baixa densidade (LDL-ox) induz à formação de epítopos imunogênicos na molécula. A presença de autoanticorpos contra a LDL-ox tem sido demonstrada no soro de pacientes com doença arterial coronariana (DAC). Contudo, o papel desses autoanticorpos na fisiopatologia das síndromes coronarianas agudas (SCA) e o seu significado clínico permanecem indefinidos. OBJETIVO: Avaliar a associação entre autoanticorpos contra a LDL-ox e SCA. MÉTODOS: Os títulos de imunoglobulina G autoanticorpos contra a LDL-ox por cobre (antiLDL-ox) e contra o peptídeo sintético D derivado da apolipoproteína B (antipeptD) foram determinados por ensaio imunoenzimático (ELISA) em 90 pacientes, nas primeiras 12h de SCA (casos) e em 90 pacientes com DAC crônica (controles). RESULTADOS: Os resultados mostraram que os títulos de antiLDL-ox foram significativamente mais elevados (p = 0,017) nos casos (0,40 ± 0,22), do que nos controles (0,33 ± 0,23). Por outro lado, os títulos de antipeptD foram significativamente menores (p < 0,01) nos casos (0,28 ± 0,23) do que nos controles (0,45 ± 0,30). A diferença dos títulos de ambos anticorpos entre os dois grupos estudados foi independente de idade, sexo, hipertensão arterial, diabete melito, dislipidemia, índice de massa corporal, tabagismo, perfil lipídico, uso de estatinas e história familiar de DAC. CONCLUSÃO: Os resultados mostraram que os títulos de antiLDL-ox foram significativamente mais elevados nos pacientes com síndrome coronariana aguda quando comparados aos pacientes com doença arterial coronariana e podem estar associados à instabilidade da placa aterosclerótica.

Effect of Pitavastatin on Vascular Reactivity in Hypercholesterolemic Rabbits

Background: Pitavastatin is the newest statin available in Brazil and likely the one with fewer side effects. Thus, pitavastatin was evaluated in hypercholesterolemic rabbits in relation to its action on vascular reactivity. Objective: To assess the lowest dose of pitavastatin necessary to reduce plasma lipids, cholesterol and tissue lipid peroxidation, as well as endothelial function in hypercholesterolemic rabbits. Methods: Thirty rabbits divided into six groups (n = 5): G1 - standard chow diet; G2 - hypercholesterolemic diet for 30 days; G3 - hypercholesterolemic diet and after the 16th day, diet supplemented with pitavastatin (0.1 mg); G4 - hypercholesterolemic diet supplemented with pitavastatin (0.25 mg); G5 - hypercholesterolemic diet supplemented with pitavastatin (0.5 mg); G6 - hypercholesterolemic diet supplemented with pitavastatin (1.0 mg). After 30 days, total cholesterol, HDL, triglycerides, glucose, creatine kinase (CK), aspartate aminotransferase (AST), alanine aminotransferase (ALT) were measured and LDL was calculated. In-depth anesthesia was performed with sodium thiopental and aortic segments were removed to study endothelial function, cholesterol and tissue lipid peroxidation. The significance level for statistical tests was 5%. Results: Total cholesterol and LDL were significantly elevated in relation to G1. HDL was significantly reduced in G4, G5 and G6 when compared to G2. Triglycerides, CK, AST, ALT, cholesterol and tissue lipid peroxidation showed no statistical difference between G2 and G3-G6. Significantly endothelial dysfunction reversion was observed in G5 and G6 when compared to G2. Conclusion: Pitavastatin starting at a 0.5 mg dose was effective in reverting endothelial dysfunction in hypercholesterolemic rabbits.

Evaluation of Sexual Dimorphism in the Efficacy and Safety of Simvastatin/Atorvastatin Therapy in a Southern Brazilian Cohort

Background: Dyslipidemia is the primary risk factor for cardiovascular disease, and statins have been effective in controlling lipid levels. Sex differences in the pharmacokinetics and pharmacodynamics of statins contribute to interindividual variations in drug efficacy and toxicity. Objective: To evaluate the presence of sexual dimorphism in the efficacy and safety of simvastatin/atorvastatin treatment. Methods: Lipid levels of 495 patients (331 women and 164 men) were measured at baseline and after 6 ± 3 months of simvastatin/atorvastatin treatment to assess the efficacy and safety profiles of both drugs. Results: Women had higher baseline levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) compared with men (p < 0.0001). After treatment, women exhibited a greater decrease in plasma TC and LDL-C levels compared with men. After adjustment for covariates, baseline levels of TC and LDL-C influenced more than 30% of the efficacy of lipid-lowering therapy (p < 0.001), regardless of sex. Myalgia [with or without changes in creatine phosphokinase (CPK) levels] occurred more frequently in women (25.9%; p = 0.002), whereas an increase in CPK and/or abnormal liver function was more frequent in in men (17.9%; p = 0.017). Conclusions: Our results show that baseline TC and LDL-C levels are the main predictors of simvastatin/atorvastatin therapy efficacy, regardless of sex. In addition, they suggest the presence of sexual dimorphism in the safety of simvastatin/atorvastatin. The effect of sex differences on receptors, transporter proteins, and gene expression pathways needs to be better evaluated and characterized to confirm these observations.

Association of Peripheral Arterial and Cardiovascular Diseases in Familial Hypercholesterolemia

Background: Familial hypercholesterolemia (FH) is an autosomal dominant genetic disease characterized by an elevation in the serum levels of total cholesterol and of low-density lipoproteins (LDL- c). Known to be closely related to the atherosclerotic process, FH can determine the development of early obstructive lesions in different arterial beds. In this context, FH has also been proposed to be a risk factor for peripheral arterial disease (PAD). Objective: This observational cross-sectional study assessed the association of PAD with other manifestations of cardiovascular disease (CVD), such as coronary artery and cerebrovascular disease, in patients with heterozygous FH. Methods: The diagnosis of PAD was established by ankle-brachial index (ABI) values ≤ 0.90. This study assessed 202 patients (35% of men) with heterozygous FH (90.6% with LDL receptor mutations), mean age of 51 ± 14 years and total cholesterol levels of 342 ± 86 mg /dL. Results: The prevalences of PAD and previous CVD were 17% and 28.2 %, respectively. On multivariate analysis, an independent association between CVD and the diagnosis of PAD was observed (OR = 2.50; 95% CI: 1.004 - 6.230; p = 0.049). Conclusion: Systematic screening for PAD by use of ABI is feasible to assess patients with FH, and it might indicate an increased risk for CVD. However, further studies are required to determine the role of ABI as a tool to assess the cardiovascular risk of those patients.

Fatty Acid and Cholesterol Concentrations in Usually Consumed Fish in Brazil

Background: Several studies have demonstrated clinical benefits of fish consumption for the cardiovascular system. These effects are attributed to the increased amounts of polyunsaturated fatty acids in these foods. However, the concentrations of fatty acids may vary according to region. Objective: The goal of this study was to determine the amount of,cholesterol and fatty acids in 10 Brazilian fishes and in a non-native farmed salmon usually consumed in Brazil. Methods: The concentrations of cholesterol and fatty acids, especially omega-3, were determined in grilled fishes. Each fish sample was divided in 3 sub-samples (chops) and each one was extracted from the fish to minimize possible differences in muscle and fat contents. Results: The largest cholesterol amount was found in white grouper (107.6 mg/100 g of fish) and the smallest in badejo (70 mg/100 g). Omega-3 amount varied from 0.01 g/100 g in badejo to 0.900 g/100 g in weakfish. Saturated fat varied from 0.687 g/100 g in seabass to 4.530 g/100 g in filhote. The salmon had the greatest concentration of polyunsaturated fats (3.29 g/100 g) and the highest content of monounsaturated was found in pescadinha (5.98 g/100 g). Whiting and boyfriend had the best omega-6/omega 3 ratios respectively 2.22 and 1.19, however these species showed very little amounts of omega-3. Conclusion: All studied Brazilian fishes and imported salmon have low amounts of saturated fat and most of them also have low amounts of omega-3.

Hemorheological and Glycemic Parameters and HDL Cholesterol for the Prediction of Cardiovascular Events

Abstract Background: Hemorheological and glycemic parameters and high density lipoprotein (HDL) cholesterol are used as biomarkers of atherosclerosis and thrombosis. Objective: To investigate the association and clinical relevance of erythrocyte sedimentation rate (ESR), fibrinogen, fasting glucose, glycated hemoglobin (HbA1c), and HDL cholesterol in the prediction of major adverse cardiovascular events (MACE) and coronary heart disease (CHD) in an outpatient population. Methods: 708 stable patients who visited the outpatient department were enrolled and followed for a mean period of 28.5 months. Patients were divided into two groups, patients without MACE and patients with MACE, which included cardiac death, acute myocardial infarction, newly diagnosed CHD, and cerebral vascular accident. We compared hemorheological and glycemic parameters and lipid profiles between the groups. Results: Patients with MACE had significantly higher ESR, fibrinogen, fasting glucose, and HbA1c, while lower HDL cholesterol compared with patients without MACE. High ESR and fibrinogen and low HDL cholesterol significantly increased the risk of MACE in multivariate regression analysis. In patients with MACE, high fibrinogen and HbA1c levels increased the risk of multivessel CHD. Furthermore, ESR and fibrinogen were significantly positively correlated with HbA1c and negatively correlated with HDL cholesterol, however not correlated with fasting glucose. Conclusion: Hemorheological abnormalities, poor glycemic control, and low HDL cholesterol are correlated with each other and could serve as simple and useful surrogate markers and predictors for MACE and CHD in outpatients.

No interaction between alcohol consumption and HDL-related genes on HDL cholesterol levels.

OBJECTIVE: To assess the relationships and possible interactions between polymorphisms related to HDL levels and alcohol consumption. METHODS: Cross-sectional population-based study including 2863 women and 2546 men aged 35-75 years (CoLaus study). Alcohol intake was assessed by the reported alcohol consumption of the last 7 days. Nineteen candidate genes known to influence HDL levels were studied. RESULTS: Alcohol consumption increased HDL cholesterol levels in both genders. After multivariate adjustment for gender, age, body mass index, smoking, hypolipidaemic drug treatment, physical activity and alcohol consumption, APOA5, CETP, LIPC and LPL gene polymorphisms were significantly (10(-5) threshold) related with HDL cholesterol levels, while no genexalcohol intake interaction was found for all SNPs studied. ABCA1 polymorphisms were related to HDL cholesterol levels on bivariate analysis but the relationship was no longer significant after multivariate analysis. CONCLUSION: Our data confirm the association of alcohol consumption and of APOA5, CETP, LIPC and LPL gene polymorphisms with HDL cholesterol levels. Conversely, no genexalcohol consumption interactions were found, suggesting that the effect of alcohol consumption on HDL cholesterol levels is not mediated via a modulation of HDL related genes.

Cholestérol, pression artérielle et fumée de cigarette dans la population en Suisse: le projet MONICA. [Cholesterol, blood-pressure and cigarette-smoking in switzerland - the MONICA-project].

Elevated plasma cholesterol, high blood pressure and cigarette smoking are three major risk factors for coronary heart disease. Within the framework of Switzerland's participation in the multicenter study MONICA (MONItoring of trends and determinants in CArdiovascular disease), proposed by the WHO, a first risk factor survey was conducted in a representative sample of the population (25-74 years) of two reporting units (cantons of Vaud and Fribourg, canton of Tessin). A high blood cholesterol level (>6,7 mmol/l) is the most common risk factor for coronary heart disease among the studied population. Among men, about 13% have elevated blood pressure, the proportion being about one in ten among women; these proportions increase with age and are slightly above these values in Tessin. Cigarette smoking is still a common behavior; between 25 and 45 years one third of the population (male and female) regularly smoke cigarettes.

Advances in pharmacological studies of silymarin

Silymarin is the flavonoids extracted from the seeds of Silybum marianum (L) Gearth as a mixture of three structural isomers: silybin, silydianin and silychristin, the former being the most active component. Silymarin protects liver cell membrane against hepatotoxic agents and improves liver function in experimental animals and humans. It is generally accepted that silymarin exerts a membrane-stabilizing action preventing or inhibiting membrane peroxidation. The experiments with soybean lipoxygenase showed that the three components of silymarin brought about a concentration-dependent non-competitive inhibition of the lipoxygenase. The experiments also showed an analogous interaction with animal lipoxygenase, thus showing that an inhibition of the peroxidation of the fatty acid in vivo was self-evident. Silybin almost completely suppressed the formation of PG at the highest concentration (0.3 mM) and proved to be an inhibitor of PG synthesis in vitro. In our experiments, silybin at lower dose (65 mg/Kg) decreased liver lipoperoxide content and microsomal lipoperoxidation to 84.5% and 68.55% of those of the scalded control rats respectively, and prevented the decrease of liver microsomal cytochrome p-450 content and p-nitroanisole-0-demethylase activity 24 h post-scalding. Effects of silymarin on cardiovascular systen have been studied in this university since 1980. O. O silymarin 800 mg/Kg/d or silybin 600 mg/Kg/d reduced plasma total cholesterol, LDL-C and VLDL-C. They however, enhanced HDL-C in hyperlipenic rats. Further studies showed that silymarin enhanced HDL-C in hyperlipemic rats. Further studies showed that silymarin enhanced HDL-C but didn't affect HDL-C, a property of this component which is beneficial to treatment of atherosclerosis. The results showed silymarin 80 mg or silybin 60 mg decreased in vitro platelet aggregation (porcentagem) in rats. The maximal platelet aggregation induced by ADP declined significantly, and time to reach maximal platelet aggregation and five-minute disaggregation didn't change. In our experiments, iv silybin 22,4 mg/kg lowered the amplitude and duration of diastolic blood pressure (DBP) more than those of systolic (SBP), but the descending aortic blood flow, cardiac contractility and ECG did not change significantly in anesthetized open-chest cats. The results indicated a reduction of peripheral resistance and dilatatory action on the resistant blood vessels. These effects are beneficial to coronary heart disease. We also observed the effects of silybin on morphological change, the release of glutamic oxaloacetate aminotrasferase (GOT) and lactate dehydrogenase (LDH) as well as the radioactivity of 3H-TdR incorporated into DNA in normal cardiac cells and cells infected by coxsackie B5, virus os newborn rats. The results showed that silynin did not affect the morphology of normal cell, and that the pathological change of cells infected by virus was delayed and reduced as compared to control. We have investigated the effect of silybin on synthesis and release of LTs in the cultured porcine cerebral basilar arteries (PCBA). Silybin 100 and 500 µmol/L declined the amounts of LTs released from the PCBA incubsated in the presence of A 23187, AA and indomenthacin. The result suggests that silybin can inhibit the activity of 5-lipoxygenase of cerebral blood vessel and may protect the brain from ischemia.

Propietats protectores de la lipoproteïna de alta densitat (HDL) sobre l'acció inflamatòria de la lipoproteïna de baixa densitat electronegativa (LDL(-)) en monòcits humans

Electronegative low-density lipoprotein (LDL(-)) is a modified fraction of LDL present in peripheral blood whose proportion is elevated in subjects with increased cardiovascular risk. LDL(-) has been shown to have an inflammatory effect on human endothelial cells and mononuclear blood cells. On the other hand, high-density lipoprotein (HDL) is known to have a protective effect against cardiovascular disease, partly mediated by its anti-inflammatory properties. The objective of the current work is to study the putative protective properties of HDL towards the inflammatory effect of LDL(-) in human monocytes, in order to elucidate the mechanisms behind their interaction. Total LDL and HDL were isolated by ultracentrifugation and LDL(-) was obtained from total LDL by anion exchange chromatography. HDL and LDL(-) were incubated together and then re-isolated, and their characteristics were compared to those of untreated lipoproteins. The inflammatory activity of the lipoproteins was determined by incubating monocytes with lipoproteins and measuring cytokine release from the cultured monocytes. The biochemical composition and electrophoretic mobility of the lipoproteins were also determined before and after their interaction. Incubation of HDL with LDL(-) reduced the inflammatory effect of LDL(-) and, in turn, HDL gained inflammatory properties. This indicates a transfer of inflammatory potential taking place during the interaction of LDL(-) and HDL. Additionally, LDL(-) lost non-esterified fatty acids (NEFAs) while HDL gained the same. We conclude that a transfer of NEFAs takes place between LDL(-) and HDL. These observations suggest that NEFAs play a role in the inflammatory effect mediated by LDL(-).

Cholesterol and sphingomyelin drive ligand-independent T-cell antigen receptor nanoclustering.

The T-cell antigen receptor (TCR) exists in monomeric and nanoclustered forms independently of antigen binding. Although the clustering is involved in the regulation of T-cell sensitivity, it is unknown how the TCR nanoclusters form. We show that cholesterol is required for TCR nanoclustering in T cells and that this clustering enhances the avidity but not the affinity of the TCR-antigen interaction. Investigating the mechanism of the nanoclustering, we found that radioactive photocholesterol specifically binds to the TCRβ chain in vivo. In order to reduce the complexity of cellular membranes, we used a synthetic biology approach and reconstituted the TCR in liposomes of defined lipid composition. Both cholesterol and sphingomyelin were required for the formation of TCR dimers in phosphatidylcholine-containing large unilamellar vesicles. Further, the TCR was localized in the liquid disordered phase in giant unilamellar vesicles. We propose a model in which cholesterol and sphingomyelin binding to the TCRβ chain causes TCR dimerization. The lipid-induced TCR nanoclustering enhances the avidity to antigen and thus might be involved in enhanced sensitivity of memory compared with naive T cells. Our work contributes to the understanding of the function of specific nonannular lipid-membrane protein interactions.